ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2962C>T (p.Arg988Cys) (rs61753795)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000232002 SCV000283775 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 988 of the MSH6 protein (p.Arg988Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs61753795, ExAC 0.009%). This variant has been reported in a family affected with Lynch syndrome (PMID: 27601186). ClinVar contains an entry for this variant (Variation ID: 237172). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be deleterious (PMID: 23621914). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000483401 SCV000567197 uncertain significance not provided 2018-02-21 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2962C>T at the cDNA level, p.Arg988Cys (R988C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant has been identified in one family suspected of having Lynch syndrome (Lagerstedt-Robinson 2016). MSH6 Arg988Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the Clamp domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Arg988Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000571603 SCV000662395 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000571603 SCV000690305 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483401 SCV001134418 uncertain significance not provided 2019-05-17 criteria provided, single submitter clinical testing

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